Over the past decade there has been a growing awareness of the disabling and treatment refractory effects of impaired cognition in schizophrenia, which results in performance deficits that are strongly and consistently related to poor functional outcome and behavioral disorganization. Along with this new awareness has come an increasing emphasis on the importance of developing new treatments that may positively impact these deficits. The MATRICS meetings built a consensus between industry, academia, and the FDA on how to move forward in the development of therapies for impaired cognition in schizophrenia. During this same period there has been an explosion of technical advances and new knowledge regarding the neural bases of cognition. Converging data from animal and human research has resulted in a dramatic increase in knowledge regarding the neurobiological mechanisms underlying normal cognition, and cognition related brain activity in humans can now readily be obtained using measures such as functional MRI, MEG and ERP. The MATRICS measures identified for use in large scale clinical trials in schizophrenia have their basis in clinical neuropsychology. These measures have the measurement properties and ease of administration needed for clinical trial settings. However, due to their complexity, they are not easily understood in terms of the brain-based models of cognition developed in cognitive neuroscience, nor are they appropriate for use in non-invasive imaging studies of the neural correlates of cognition. To begin to develop a brain based set of tools for measuring cognition in schizophrenia, we initiated the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) process, funded by the R13 mechanism. The first phase of CNTRICS focused on enhancing the identification of cognitive targets from a cognitive neuroscience perspective, and then addressing critical measurement challenges associated with the use of these approaches in the drug development setting. We then identified of a set of tasks from cognitive neuroscience that are considered valid measures of the cognitive deficits targeted for intervention in schizophrenia. The results of the first two CNTRICS meetings have been published (in Biological Psychiatry and Schizophrenia Bulletin respectively)[5, 6] and the results of the third are in the process of being published in Schizophrenia Bulletin. An RFA followed the first meeting and a number of RO1's will be funded to refine and optimize tasks based upon the outcome of the CNTRICS process. There is anticipation of a future program announcement for ongoing translational research developing and adapting additional tasks from basic cognitive neuroscience for use in treatment development for impaired cognition in schizophrenia. In this competing renewal we propose to build on the initial progress made during the first three CNTRICS meetings, focusing on two areas where innovation may significantly enhance translational research and the treatment development process. The first of these is the identification and development of in vivo neural systems measures from non-invasive neuroimaging to serve as biomarkers/surrogate markers of treatment effects. The second is the development of new animal models that target processes most relevant for impaired cognitive and emotional processing in schizophrenia. Progress in these two areas will lead to a more integrated process of treatment development in which preclinical studies are more seamlessly integrated with early phase human studies. To accomplish this goal we will pursue the following two Specific Aims by organizing four conferences over a three-year period. There has been a recent explosion of new knowledge from the new field of cognitive neuroscience about how the brain supports human cognition. However most research approaches for developing treatments for cognitive deficits in schizophrenia use older clinical neuropsychological tasks which pre-date cognitive neuroscience and do not measure cognitive processes linked to discrete neural processes. This project involves organizing four meetings designed to build on the progress made during the initial funding period by identifying a set of new, non invasive cognitive neuroimaging measures for use in human subjects together with a related set of valid animal models of cognition relevant for impaired cognition in schizophrenia. These new human imaging tools and animal models will lead to enhanced "vertically integrated" translational research targeting impaired cognition in schizophrenia.